Gpcr inhibitors and uses thereof

Abstract

This invention relates to methods and compositions directed to mobilizing a cell in a subject by blocking CXCR4, a beta-adrenergic receptor, a GPCR, or any combination thereof. In some embodiments, the cell is a stem cell. In some embodiments, the cell is an immune cell.

1 - 89 . (canceled) 
     
     
         90 . A method for treatment of cancer comprising administering, alone or in combination, a CXCR4 inhibitor and a beta-2-adrenergic receptor (ADRB2) inhibitor to a subject, wherein the treatment comprises stem cell transplantation. 
     
     
         91 . The method of  claim 90 , wherein the administering comprises administering the ADRB2 inhibitor and the CXCR4 inhibitor simultaneously, concurrently, or sequentially to the subject. 
     
     
         92 . The method of  claim 90 , wherein the administering comprises administering the ADRB2 inhibitor to the subject before administering the CXCR4 inhibitor to the subject. 
     
     
         93 . The method of  claim 90 , wherein administering the ADRB2 inhibitor is initiated at a first specific time interval before administering the CXCR4 inhibitor, and wherein the first specific time interval is 6 days to 7 days. 
     
     
         94 . The method of  claim 90 , wherein the treatment comprises hematopoietic stem cell transplantation or hematopoietic progenitor cell transplantation. 
     
     
         95 . The method of  claim 90 , wherein the stem cell transplantation comprises autologous stem cell transplantation. 
     
     
         96 . The method of  claim 90 , wherein the stem cell transplantation comprises allogeneic stem cell transplantation. 
     
     
         97 . The method of  claim 90 , wherein the cancer is selected from lymphoma, leukemia, and myeloma. 
     
     
         98 . The method of  claim 90 , wherein the cancer is selected from non-Hodgkin lymphoma, acute myeloid leukemia, acute lymphoblastic leukemia, and multiple myeloma. 
     
     
         99 . The method of  claim 90 , wherein the cancer is multiple myeloma. 
     
     
         100 . The method of  claim 90 , wherein the CXCR4 inhibitor is selected from the group consisting of ALX40-4C, AMD070, plerixafor, AMD3465, ATI 2341, BKT140, CTCE-9908, CX549, D-[Lys3] GHRP-6, FC122, FC131, GMI-1359, GSK812397, GST-NT21MP, isothiourea-la, isothiourea-It (IT1t), KRH-1636, KRH-3955, LY2510924, MSX-122, N-[11C] Methyl-AMD3465, POL6326, SDF-1 1-9 [P2G] dimer, SDF1 P2G, T134, T140, T22, TC 14012, burixafor, USL311, viral macrophage inflammatory protein-II, WZ811, [64Cu]-AMD3100, [64Cu]-AMD3465, [68Ga] pentixafor, [90Y] pentixather, [99mTc] 02-AMD3100, [177Lu] pentixather, and 508MC1 Compound 26. 
     
     
         101 . The method of  claim 90 , wherein the CXCR4 inhibitor is selected from burixafor, plerixafor, and ulocuplumab. 
     
     
         102 . The method of  claim 90 , wherein the CXCR4 inhibitor is burixafor. 
     
     
         103 . The method of  claim 90 , wherein the ADRB2 inhibitor is selected from the group consisting of alprenolol, atenolol, betaxolol, bupranolol, butoxamine, carazolol, carvedilol, CGP 12177, cicloprolol, ICI 118551, ICYP, labetalol, levobetaxolol, levobunolol, LK 204-545, metoprolol, nadolol, NIHP, NIP, propafenone, propranolol, sotalol, SR59230A, and timolol. 
     
     
         104 . The method of  claim 90 , wherein the ADRB2 inhibitor is propranolol. 
     
     
         105 . The method of  claim 90 , wherein the CXCR4 inhibitor is selected from the group consisting of burixafor, plerixafor, and ulocuplumab, and wherein the ADRB2 inhibitor is propranolol. 
     
     
         106 . The method of  claim 90 , wherein the CXCR4 inhibitor is burixafor, and wherein the ADRB2 inhibitor is propranolol. 
     
     
         107 . The method of  claim 90 , wherein the method further comprises administering G-CSF to the subject. 
     
     
         108 . The method of  claim 90 , wherein the method does not comprise administering G-CSF to the subject. 
     
     
         109 . The method of  claim 90 , wherein the CXCR4 inhibitor is burixafor, wherein the ADRB2 inhibitor is propranolol, wherein the cancer is multiple myeloma, and wherein the treatment further comprises administration of G-CSF. 
     
     
         110 . The method of  claim 90 , wherein the CXCR4 inhibitor is burixafor, wherein the ADRB2 inhibitor is propranolol, wherein the cancer is multiple myeloma, and wherein the treatment does not comprise administration of G-CSF. 
     
     
         111 . The method of  claim 90 , wherein the CXCR4 inhibitor is burixafor, wherein the ADRB2 inhibitor is propranolol, wherein the cancer is multiple myeloma, wherein the stem cell transplantation comprises autologous stem cell transplantation, and wherein the treatment comprises administration of G-CSF. 
     
     
         112 . The method of  claim 90 , wherein the CXCR4 inhibitor is burixafor, wherein the ADRB2 inhibitor is propranolol, wherein the cancer is multiple myeloma, wherein the stem cell transplantation comprises autologous stem cell transplantation, and wherein the treatment does not comprise administration of G-CSF. 
     
     
         113 . The method of  claim 90 , wherein the CXCR4 inhibitor is burixafor, wherein the ADRB2 inhibitor is propranolol, wherein the cancer is multiple myeloma, wherein the stem cell transplantation comprises allogeneic stem cell transplantation, and wherein the treatment comprises administration of G-CSF. 
     
     
         114 . The method of  claim 90 , wherein the CXCR4 inhibitor is burixafor, wherein the ADRB2 inhibitor is propranolol, wherein the cancer is multiple myeloma, wherein the stem cell transplantation comprises allogeneic stem cell transplantation, and wherein the treatment does not comprise administration of G-CSF. 
     
     
         115 . A composition or compositions for treatment of cancer comprising, alone or in combination, a CXCR4 inhibitor and a beta-2-adrenergic receptor (ADRB2) inhibitor, wherein the treatment comprises stem cell transplantation. 
     
     
         116 . The composition or compositions of  claim 115 , wherein the treatment comprises hematopoietic stem cell transplantation or hematopoietic progenitor cell transplantation. 
     
     
         117 . The composition or compositions of  claim 115 , wherein the stem cell transplantation comprises autologous stem cell transplantation. 
     
     
         118 . The composition or compositions of  claim 115 , wherein the stem cell transplantation comprises allogeneic stem cell transplantation. 
     
     
         119 . The composition or compositions of  claim 115 , wherein the cancer is selected from lymphoma, leukemia, or myeloma. 
     
     
         120 . The composition or compositions of  claim 115 , wherein the cancer is selected from non-Hodgkin lymphoma, acute myeloid leukemia, acute lymphoblastic leukemia, or multiple myeloma. 
     
     
         121 . The composition or compositions of  claim 115 , wherein the cancer is multiple myeloma. 
     
     
         122 . The composition or compositions of  claim 115 , wherein the CXCR4 inhibitor is selected from the group consisting of ALX40-4C, AMD070, plerixafor, AMD3465, ATI 2341, BKT140, CTCE-9908, CX549, D-[Lys3] GHRP-6, FC122, FC131, GMI-1359, GSK812397, GST-NT21MP, isothiourea-la, isothiourea-It (IT1t), KRH-1636, KRH-3955, LY2510924, MSX-122, N-[11C] Methyl-AMD3465, POL6326, SDF-1 1-9 [P2G] dimer, SDF1 P2G, T134, T140, T22, TC 14012, burixafor, USL311, viral macrophage inflammatory protein-II, WZ811, [64Cu]-AMD3100, [64Cu]-AMD3465, [68Ga] pentixafor, [90Y] pentixather, [99mTc] 02-AMD3100, [177Lu] pentixather, and 508MC1 Compound 26. 
     
     
         123 . The composition or compositions of  claim 115 , wherein the CXCR4 inhibitor is selected from burixafor, plerixafor, and ulocuplumab. 
     
     
         124 . The composition or compositions of  claim 115 , wherein the CXCR4 inhibitor is burixafor. 
     
     
         125 . The composition or compositions of  claim 115 , wherein the ADRB2 inhibitor is selected from the group consisting of alprenolol, atenolol, betaxolol, bupranolol, butoxamine, carazolol, carvedilol, CGP 12177, cicloprolol, ICI 118551, ICYP, labetalol, levobetaxolol, levobunolol, LK 204-545, metoprolol, nadolol, NIHP, NIP, propafenone, propranolol, sotalol, SR59230A, and timolol. 
     
     
         126 . The composition or compositions of  claim 115 , wherein the ADRB2 inhibitor is propranolol. 
     
     
         127 . The composition or compositions of  claim 115 , wherein the CXCR4 inhibitor is selected from the group consisting of burixafor, plerixafor, and ulocuplumab, and wherein the ADRB2 inhibitor is propranolol. 
     
     
         128 . The composition or compositions of  claim 115 , wherein the CXCR4 inhibitor is burixafor, and wherein the ADRB2 inhibitor is propranolol. 
     
     
         129 . The composition or compositions of  claim 115 , wherein the CXCR4 inhibitor is burixafor, wherein the ADRB2 inhibitor is propranolol, wherein the cancer is multiple myeloma, and wherein the composition or compositions further comprise G-CSF. 
     
     
         130 . The composition or compositions of  claim 115 , wherein the CXCR4 inhibitor is burixafor, wherein the ADRB2 inhibitor is propranolol, wherein the cancer is multiple myeloma, and wherein the composition or compositions do not comprise G-CSF. 
     
     
         131 . The composition or compositions of  claim 115 , wherein the CXCR4 inhibitor is burixafor, wherein the ADRB2 inhibitor is propranolol, wherein the cancer is multiple myeloma, wherein the stem cell transplantation comprises autologous stem cell transplantation, and wherein the composition or compositions further comprise G-CSF. 
     
     
         132 . The composition or compositions of  claim 115 , wherein the CXCR4 inhibitor is burixafor, wherein the ADRB2 inhibitor is propranolol, wherein the cancer is multiple myeloma, wherein the stem cell transplantation comprises autologous stem cell transplantation, and wherein the composition or compositions do not comprise G-CSF. 
     
     
         133 . The composition or compositions of  claim 115 , wherein the CXCR4 inhibitor is burixafor, wherein the ADRB2 inhibitor is propranolol, wherein the cancer is multiple myeloma, wherein the stem cell transplantation comprises allogeneic stem cell transplantation, and wherein the composition or compositions further comprise G-CSF. 
     
     
         134 . The composition or compositions of  claim 115 , wherein the CXCR4 inhibitor is burixafor, wherein the ADRB2 inhibitor is propranolol, wherein the cancer is multiple myeloma, wherein the stem cell transplantation comprises allogeneic stem cell transplantation, and wherein the composition or compositions do not comprise G-CSF. 
     
     
         135 . A pharmaceutical composition or pharmaceutical compositions for treatment of cancer comprising, alone or in combination, a CXCR4 inhibitor and a beta-2-adrenergic receptor (ADBR2), and a pharmaceutically acceptable excipient, wherein the treatment comprises stem cell transplantation. 
     
     
         136 . The pharmaceutical composition or compositions of  claim 135 , wherein the treatment comprises hematopoietic stem cell transplantation or hematopoietic progenitor cell transplantation. 
     
     
         137 . The pharmaceutical composition or compositions of  claim 135 , wherein the stem cell transplantation comprises autologous stem cell transplantation. 
     
     
         138 . The pharmaceutical composition or compositions of  claim 135 , wherein the stem cell transplantation comprises allogeneic stem cell transplantation. 
     
     
         139 . The pharmaceutical composition or compositions of  claim 135 , wherein the cancer is selected from lymphoma, leukemia, or myeloma. 
     
     
         140 . The pharmaceutical composition or compositions of  claim 135 , wherein the cancer is selected from non-Hodgkin lymphoma, acute myeloid leukemia, acute lymphoblastic leukemia, or multiple myeloma. 
     
     
         141 . The pharmaceutical composition or compositions of  claim 135 , wherein the cancer is multiple myeloma. 
     
     
         142 . The pharmaceutical composition or compositions of  claim 135 , wherein the CXCR4 inhibitor is selected from the group consisting of ALX40-4C, AMD070, plerixafor, AMD3465, ATI 2341, BKT140, CTCE-9908, CX549, D-[Lys3] GHRP-6, FC122, FC131, GMI-1359, GSK812397, GST-NT21MP, isothiourea-la, isothiourea-It (IT1t), KRH-1636, KRH-3955, LY2510924, MSX-122, N-[11C] Methyl-AMD3465, POL6326, SDF-1 1-9 [P2G] dimer, SDF1 P2G, T134, T140, T22, TC 14012, burixafor, USL311, viral macrophage inflammatory protein-II, WZ811, [64Cu]-AMD3100, [64Cu]-AMD3465, [68Ga] pentixafor, [90Y] pentixather, [99mTc] 02-AMD3100, [177Lu] pentixather, and 508MC1 Compound 26. 
     
     
         143 . The pharmaceutical composition or compositions of  claim 135 , wherein the CXCR4 inhibitor is selected from burixafor, plerixafor, and ulocuplumab. 
     
     
         144 . The pharmaceutical composition or compositions of  claim 135 , wherein the CXCR4 inhibitor is burixafor. 
     
     
         145 . The pharmaceutical composition or compositions of  claim 135 , wherein the ADRB2 inhibitor is selected from the group consisting of alprenolol, atenolol, betaxolol, bupranolol, butoxamine, carazolol, carvedilol, CGP 12177, cicloprolol, ICI 118551, ICYP, labetalol, levobetaxolol, levobunolol, LK 204-545, metoprolol, nadolol, NIHP, NIP, propafenone, propranolol, sotalol, SR59230A, and timolol. 
     
     
         146 . The pharmaceutical composition or compositions of  claim 135 , wherein the ADRB2 inhibitor is propranolol. 
     
     
         147 . The pharmaceutical composition or compositions of  claim 135 , wherein the CXCR4 inhibitor is selected from the group consisting of burixafor, plerixafor, and ulocuplumab, and wherein the ADRB2 inhibitor is propranolol. 
     
     
         148 . The pharmaceutical composition or compositions of  claim 135 , wherein the CXCR4 inhibitor is burixafor, and wherein the ADRB2 inhibitor is propranolol. 
     
     
         149 . The pharmaceutical composition or compositions of  claim 135 , wherein the CXCR4 inhibitor is burixafor, wherein the ADRB2 inhibitor is propranolol, wherein the cancer is multiple myeloma, and wherein the pharmaceutical composition or pharmaceutical compositions further comprise G-CSF. 
     
     
         150 . The pharmaceutical composition or compositions of  claim 135 , wherein the CXCR4 inhibitor is burixafor, wherein the ADRB2 inhibitor is propranolol, wherein the cancer is multiple myeloma, and wherein the pharmaceutical composition or pharmaceutical compositions do not comprise G-CSF. 
     
     
         151 . The pharmaceutical composition or compositions of  claim 135 , wherein the CXCR4 inhibitor is burixafor, wherein the ADRB2 inhibitor is propranolol, wherein the cancer is multiple myeloma, wherein the stem cell transplantation comprises autologous stem cell transplantation, and wherein the pharmaceutical composition or pharmaceutical compositions further comprise G-CSF. 
     
     
         152 . The pharmaceutical composition or compositions of  claim 135 , wherein the CXCR4 inhibitor is burixafor, wherein the ADRB2 inhibitor is propranolol, wherein the cancer is multiple myeloma, wherein the stem cell transplantation comprises autologous stem cell transplantation, and wherein the pharmaceutical composition or pharmaceutical compositions do not comprise G-CSF. 
     
     
         153 . The pharmaceutical composition or compositions of  claim 135 , wherein the CXCR4 inhibitor is burixafor, wherein the ADRB2 inhibitor is propranolol, wherein the cancer is multiple myeloma, wherein the stem cell transplantation comprises allogeneic stem cell transplantation, and wherein the pharmaceutical composition or pharmaceutical compositions further comprise G-CSF. 
     
     
         154 . The pharmaceutical composition or compositions of  claim 135 , wherein the CXCR4 inhibitor is burixafor, wherein the ADRB2 inhibitor is propranolol, wherein the cancer is multiple myeloma, wherein the stem cell transplantation comprises allogeneic stem cell transplantation, and wherein the pharmaceutical composition or pharmaceutical compositions do not comprise G-CSF. 
     
     
         155 . A method of mobilizing a cell in a subject comprising administering, alone or in combination, a CXCR4 inhibitor and a beta-2-adrenergic receptor (ADRB2) inhibitor to a subject. 
     
     
         156 . The method of  claim 155 , wherein the administering comprises administering the ADRB2 inhibitor and the CXCR4 inhibitor simultaneously, concurrently, or sequentially to the subject. 
     
     
         157 . The method of  claim 155 , wherein the administering comprises administering the ADRB2 inhibitor to the subject before administering the CXCR4 inhibitor to the subject. 
     
     
         158 . The method of  claim 155 , wherein administering the ADRB2 inhibitor is initiated at a first specific time interval before administering the CXCR4 inhibitor, and wherein the first specific time interval is 6 days to 7 days. 
     
     
         159 . The method of  claim 155 , wherein the cell is a stem cell. 
     
     
         160 . The method of  claim 155 , wherein the cell is a stem cell, and wherein the mobilizing is used for treatment of cancer, and wherein the treatment comprises stem cell transplantation. 
     
     
         161 . The method of  claim 160 , wherein the treatment comprises hematopoietic stem cell transplantation or hematopoietic progenitor cell transplantation. 
     
     
         162 . The method of  claim 160 , wherein the stem cell transplantation comprises autologous stem cell transplantation. 
     
     
         163 . The method of  claim 160 , wherein the stem cell transplantation comprises allogeneic stem cell transplantation. 
     
     
         164 . The method of  claim 160 , wherein the cancer is selected from lymphoma, leukemia, and myeloma. 
     
     
         165 . The method of  claim 160 , wherein the cancer is selected from non-Hodgkin lymphoma, acute myeloid leukemia, acute lymphoblastic leukemia, and multiple myeloma. 
     
     
         166 . The method of  claim 160 , wherein the cancer is multiple myeloma. 
     
     
         167 . The method of  claim 155 , wherein the CXCR4 inhibitor is selected from the group consisting of ALX40-4C, AMD070, plerixafor, AMD3465, ATI 2341, BKT140, CTCE-9908, CX549, D-[Lys3] GHRP-6, FC122, FC131, GMI-1359, GSK812397, GST-NT21MP, isothiourea-la, isothiourea-It (IT1t), KRH-1636, KRH-3955, LY2510924, MSX-122, N-[11C] Methyl-AMD3465, POL6326, SDF-1 1-9 [P2G] dimer, SDF1 P2G, T134, T140, T22, TC 14012, burixafor, USL311, viral macrophage inflammatory protein-II, WZ811, [6Cu]-AMD3100, [64Cu]-AMD3465, [68Ga] pentixafor, [90Y] pentixather, [ 99m Tc] 02-AMD3100, [177Lu] pentixather, and 508MC1 Compound 26. 
     
     
         168 . The method of  claim 155 , wherein the CXCR4 inhibitor is selected from burixafor, plerixafor, and ulocuplumab. 
     
     
         169 . The method of  claim 155 , wherein the CXCR4 inhibitor is burixafor. 
     
     
         170 . The method of  claim 155 , wherein the ADRB2 inhibitor is selected from the group consisting of alprenolol, atenolol, betaxolol, bupranolol, butoxamine, carazolol, carvedilol, CGP 12177, cicloprolol, ICI 118551, ICYP, labetalol, levobetaxolol, levobunolol, LK 204-545, metoprolol, nadolol, NIHP, NIP, propafenone, propranolol, sotalol, SR59230A, and timolol. 
     
     
         171 . The method of  claim 155 , wherein the ADRB2 inhibitor is propranolol. 
     
     
         172 . The method of  claim 155 , wherein the CXCR4 inhibitor is selected from the group consisting of burixafor, plerixafor, and ulocuplumab, and wherein the ADRB2 inhibitor is propranolol. 
     
     
         173 . The method of  claim 155 , wherein the CXCR4 inhibitor is burixafor, and wherein the ADRB2 inhibitor is propranolol. 
     
     
         174 . The method of  claim 155 , wherein the method further comprises administering G-CSF to the subject. 
     
     
         175 . The method of  claim 155 , wherein the method does not comprise administering G-CSF to the subject. 
     
     
         176 . The method of  claim 160 , wherein the CXCR4 inhibitor is burixafor, wherein the ADRB2 inhibitor is propranolol, wherein the cancer is multiple myeloma, and wherein the treatment further comprises administration of G-CSF. 
     
     
         177 . The method of  claim 160 , wherein the CXCR4 inhibitor is burixafor, wherein the ADRB2 inhibitor is propranolol, wherein the cancer is multiple myeloma, and wherein the treatment does not comprise administration of G-CSF. 
     
     
         178 . The method of  claim 160 , wherein the CXCR4 inhibitor is burixafor, wherein the ADRB2 inhibitor is propranolol, wherein the cancer is multiple myeloma, wherein the stem cell transplantation comprises autologous stem cell transplantation, and wherein the treatment comprises administration of G-CSF. 
     
     
         179 . The method of  claim 160 , wherein the CXCR4 inhibitor is burixafor, wherein the ADRB2 inhibitor is propranolol, wherein the cancer is multiple myeloma, wherein the stem cell transplantation comprises autologous stem cell transplantation, and wherein the treatment does not comprise administration of G-CSF. 
     
     
         180 . The method of  claim 160 , wherein the CXCR4 inhibitor is burixafor, wherein the ADRB2 inhibitor is propranolol, wherein the cancer is multiple myeloma, wherein the stem cell transplantation comprises allogeneic stem cell transplantation, and wherein the treatment comprises administration of G-CSF. 
     
     
         181 . The method of  claim 160 , wherein the CXCR4 inhibitor is burixafor, wherein the ADRB2 inhibitor is propranolol, wherein the cancer is multiple myeloma, wherein the stem cell transplantation comprises allogeneic stem cell transplantation, and wherein the treatment does not comprise administration of G-CSF.